Nuclear factor-kappaB dependency of doxorubicin sensitivity in gastric cancer cells is determined by manganese superoxide dismutase expression

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Cho, Sung Jin; Park, Jong-Wan; Kang, Jae Seung; Kim, Woo Ho; Juhnn, Yong-Sung; Lee, Jae-Seon; Kim, Young-Hoon; Ko, Yong San; Nam, Seon Young; Lee, Byung Lan
Issue Date
Japanese Cancer Association = 日本癌学会 ;
Cancer Sci 2008; 99: 1117-24
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The role of nuclear factor-kappaB (NF-kappaB) activation in cancer cell apoptosis appears to be tailored specifically for each cell type and the type of NF-kappaB inducer. The present study aimed to determine whether or not NF-kappaB activation is associated with chemosensitivity to doxorubicin (DOX) using the DOX-sensitive SNU-601 and DOX-resistant SNU-216 gastric cancer cell lines. The effect of NF-kappaB activation on DOX (1 microg/mL) sensitivity was analyzed after the suppression of NF-kappaB activation using transfection of the super-suppressive mutant form of IkappaBalpha (mIkappaBalpha) or pretreatment with pyrrolidine dithiocarbamate. In addition, the association between NF-kappaB and manganese superoxide dismutase (MnSOD) in relation to DOX sensitivity was analyzed after the modulation of MnSOD expression. The NF-kappaB activity was much higher in DOX-resistant SNU-216 cells than in DOX-sensitive SNU-601 cells before and after DOX treatment. Overexpression of mIkappaBalpha or pyrrolidine dithiocarbamate pretreatment decreased the DOX resistance in SNU-601 cells with low MnSOD expression, but not in SNU-216 cells with high MnSOD expression. In comparison, the overexpression of MnSOD, which also suppressed NF-kappaB activation in both cell lines, increased DOX resistance in SNU-601 cells. Blocking of MnSOD expression using RNA interference techniques increased DOX sensitivity in SNU-216 cells, which was further augmented by the additional inhibition of NF-kappaB activity. Our results showed that whether NF-kappaB contributes to DOX sensitivity in gastric cancer cells is determined by the level of MnSOD expression. Thus, targeting both MnSOD and NF-kappaB may be helpful for increasing the efficacy of DOX treatment of DOX-resistant SNU gastric cancer cells.
1347-9032 (print)
1349-7006 (online)
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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